More than 60 million people have been infected with the human immunodeficiency virus (“HIV”), the causative agent of acquired immune deficiency syndrome (“AIDS”), since the early 1980s. See Lucas, 2002, Lepr Rev. 73(1):64-71. HIV/AIDS is now the leading cause of death in sub-Saharan Africa, and is the fourth biggest killer worldwide. At the end of 2001, an estimated 40 million people were living with HIV globally. See Norris, 2002, Radiol Technol. 73(4):339-363.
Modern anti-HIV drugs target different stages of the HIV life cycle and a variety of enzymes essential for HIV's replication and/or survival. Amongst the drugs that have so far been approved for AIDS therapy are nucleoside reverse transcriptase inhibitors (“NRTIs”) such as AZT, ddI, ddC, d4T, 3TC, and abacavir; nucleotide reverse transcriptase inhibitors such as tenofovir; non-nucleoside reverse transcriptase inhibitors (“NNRTIs”) such as nevirapine, efavirenz, and delavirdine; protease inhibitors (“PIs”) such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir and atazanavir; and fusion inhibitors, such as enfuvirtide. In addition, a number of drugs in other classes are currently under investigation for their ability to effectively treat HIV infection. Among such drugs are integrase strand transfer inhibitors (“INSTIs”) such as the diketo acids diketo acid 1 and diketo acid 2 and the napthyridine carboximides L-870,810 and MK0518.
Nonetheless, in the vast majority of subjects none of these antiviral drugs, either alone or in combination, proves effective either to prevent eventual progression of chronic HIV infection to AIDS or to treat acute AIDS. This phenomenon is due, in part, to the high mutation rate of HIV and the rapid emergence of mutant HIV strains that are resistant to antiviral therapeutics upon administration of such drugs to infected individuals.
Many such mutant strains have been characterized in order to correlate presence of the mutations in the strains with resistant or susceptible phenotypes. For example, the K103N mutation in reverse transcriptase is known to correlate with resistance to a number of NNRTIs. See, e.g., De Clercq, 1997, Int'l J. of Antimicrobial Agents 9:21-36. In addition, the P225H mutation in reverse transcriptase is also known to correlate with resistance to HIV-1 specific reverse transcriptase inhibitors (RTI). See, e.g., Pelemans et al., 1998, J. Gen. Virol. 79(Pt6):1347-52. Thus, a given mutation may correlate with resistance to one or more antiviral agents.
Though numerous mutations associated with resistance to particular anti-viral agents have been identified, the complete set of mutations associated with resistance to NNRTIs, to NRTIs, and to INSTIs has not been identified. Further, in view of the clinical relevance of NRTI, NNRTI, and INSTI resistance, a more complete understanding of mutations associated with such resistance is also needed. Thus, there remains a need to identify additional mutations associated with resistance to NRTIs, NNRTIs, and INSTIs and to characterize these mutations. For the first time, these, as well as other unmet needs, will be achievable as a result of the invention described hereinafter.